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Abstract:

The present invention relates to pharmaceutical compositions that include
a combination of a biguanide present in an extended-release form and a
low dose antidiabetic agent present in an immediate-release form. The
present invention further relates to processes for preparing such
compositions.

Claims:

1. A pharmaceutical composition of a biguanide and a low dose
antidiabetic agent comprising: (i) a biguanide core comprising a
therapeutically effective amount of a biguanide or its pharmaceutically
effective salts and one or more pharmaceutically acceptable excipients;
(ii) optionally a seal coat; (iii) an extended-release coat comprising
one or more rate-controlling materials wherein there is no passageway in
the coat; (iv) optionally a second seal coat; (v) a low dose antidiabetic
agent coat comprising a therapeutically effective amount of a low dose
antidiabetic agent or its pharmaceutically effective salts and one or
more pharmaceutically acceptable excipients; and (vi) optionally a film
coat.

3. The pharmaceutical composition according to claim 1, wherein the low
dose antidiabetic agent is selected from DPP-IV inhibitors, meglitinides,
second generation sulphonylureas, glucagon-like peptide (GLP-1)
analogues, other hypoglycemics which are used as an adjunct to metformin
therapy, or mixtures thereof.

4. The pharmaceutical composition according to claim 1, wherein the
biguanide is metformin and the low dose antidiabetic agent is a DPP-IV
inhibitor.

5. The pharmaceutical composition according to claim 1, wherein the
biguanide is layered onto a pharmaceutically inert core or seed.

6. The pharmaceutical composition according to claim 5, wherein the inert
core or seed is hydrosoluble or hydroinsoluble.

7. The pharmaceutical composition according to claim 1, wherein the
biguanide core comprises one or more pharmaceutically acceptable
excipients selected from one or more of fillers, binders, disintegrants,
anti adherents, lubricants, glidants, osmogents, coloring agents, and
flavoring agents.

8. The pharmaceutical composition according to claim 1, wherein the
biguanide core additionally contains one or more absorption enhancers.

9. The pharmaceutical composition according to claim 1, wherein the
biguanide core additionally contains one or more swellable polymers.

10. The pharmaceutical composition according to claim 1, wherein the seal
coat is applied over the biguanide core or over the extended-release
coat.

11. The pharmaceutical composition according to claim 1, wherein the
biguanide core further comprises a low dose antidiabetic agent.

12. The pharmaceutical composition according to claim 1, wherein the low
dose antidiabetic agent coat further comprises a biguanide.

13. The pharmaceutical composition of claim 1, wherein the biguanide core
further comprises a low-dose antidiabetic agent, and the low-dose
antidiabetic agent coat further comprises a biguanide.

14. The pharmaceutical composition according to claim 1, wherein the
rate-controlling material is selected from one or more of hydrophilic
polymers, hydrophobic polymers, water swellable polymers, other
hydrophobic materials, or mixtures thereof.

15. A pharmaceutical composition of a biguanide and a low dose
antidiabetic agent that includes: (i) a biguanide core which includes a
therapeutically effective amount of biguanide or its pharmaceutically
effective salts and one or more pharmaceutically acceptable excipients;
(ii) optionally a seal coat; (iii) an extended-release coat which
includes one or more rate-controlling materials wherein there is no
passageway in the coat; (iv) optionally a second seal coat; (v) an
immediate-release drug coat which includes a biguanide and a low dose
antidiabetic agent or its pharmaceutically effective salt and one or more
pharmaceutically acceptable excipients; and (vi) optionally a film coat.

16. The pharmaceutical composition according to claim 15, wherein the
ratio of biguanide in the core to that in the coat ranges from about 99:1
to about 60:40.

17. A process for preparing a pharmaceutical composition comprising the
steps of: (i) preparing the cores which include a biguanide or its
pharmaceutically effective salts and one or more pharmaceutically
acceptable excipients; (ii) optionally coating the cores with a seal
coat; (iii) coating the biguanide cores of step (ii) with an
extended-release coating composition which includes one or more
rate-controlling materials; (iv) coating the extended-release core with
an immediate-release coating composition which includes a low dose
antidiabetic agent or its pharmaceutically effective salts and one or
more pharmaceutically acceptable excipients; and (v) optionally providing
a film coat.

18. A method for treating diabetes by administering to a person in need
thereof a pharmaceutical composition of a biguanide and a low dose
antidiabetic agent comprising: (i) a biguanide core which includes a
therapeutically effective amount of biguanide or its pharmaceutically
effective salts and one or more pharmaceutically acceptable excipients;
(ii) optionally a seal coat; (iii) an extended-release coat which
includes one or more rate-controlling materials wherein there is no
passageway in the coat; (iv) a low dose antidiabetic agent coat which
includes a therapeutically effective amount of a low dose antidiabetic
agent or its pharmaceutically effective salts and one or more
pharmaceutically acceptable excipients; and (v) optionally a film coat.

19. The method for treating diabetes according to claim 18, wherein the
low dose antidiabetic agent is a DPP-IV inhibitor.

Description:

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of application Ser. No.
13/193,705 claiming priority of Indian Patent Application Nos.
1811/DEL/2010 filed on Jul. 30, 2010 and 842/DEL/2011 filed on Mar. 25,
2011, all of which are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to pharmaceutical compositions that
include a combination of a biguanide present in an extended-release form
and a low dose antidiabetic agent present in an immediate-release form.
The present invention further relates to processes for preparing such
compositions.

BACKGROUND OF THE INVENTION

[0003] Two major forms of diabetes mellitus are now recognized: Type I and
Type II. Type I diabetes, or insulin-dependent diabetes, is the result of
an absolute deficiency of insulin, the hormone that regulates glucose
utilization; patients with Type I diabetes are dependent on exogenous
insulin for survival. Type II diabetes, or non-insulin-dependent diabetes
(NIDDM), often occurs concurrent with normal, or even elevated levels of
insulin, and appears to be the result of the inability of tissues to
respond appropriately to insulin (i.e., insulin resistance). Insulin
resistance is a major susceptibility trait of NIDDM and also is a
contributing factor in arteriosclerosis, hypertension, lipid disorders,
and polycystic ovarian syndrome.

[0004] Biguanides have been the most widely used class of antidiabetics.
They act by increasing insulin activity in peripheral tissues, reducing
hepatic glucose output due to inhibition of gluconeogenesis, and reducing
the absorption of glucose from the intestine. Metformin, phenformin,
buformin, etc. belong to this group. Metformin has been widely prescribed
for lowering blood glucose in patients with NIDDM and is marketed in 500,
750, 850, and 1000 mg strengths. However, because it is a short acting
drug, metformin requires twice-daily or three-times-daily dosing (500-850
mg tab 2-3 times per day or 1000 mg tab twice per day with meals).
Adverse events associated with metformin include anorexia, nausea,
vomiting and diarrhea. The adverse events may be partially avoided by
taking an extended-release dosage form rather than multiple daily doses.
Besides reducing the adverse events, administering an extended-release
dosage form provides a reduction in the frequency of administration.
However, to formulate a high dose biguanide like metformin HCl 1000 mg in
an extended-release dosage form poses a challenge due to the large size
of the dosage form. Further, the use of metformin therapy is limited by
the decline in the duration of its efficacy. This problem can be solved
by using a biguanide in combination with other antidiabetic agents.

[0005] Since the various antidiabetic agents act by different mechanisms,
a combination therapy of a biguanide and an additional antidiabetic agent
would have greater efficacy (an additive and/or synergistic effect) and
as well as the possibility of reducing the adverse events as a result of
using lower doses.

[0006] There are many low dose antidiabetic agents known which can be used
in combination with a biguanide in an immediate-release form and enhance
its efficacy and reduce the adverse events. The low dose antidiabetic
agents include but are not limited to thiazolidinediones such as
troglitazone, rosiglitazone, and pioglitazone; dipeptidyl peptidase-IV
(DPP-IV) inhibitors such as sitagliptin, linagliptin, vildagliptin,
saxagliptin, alogliptin, and dutogliptin; meglitinides such as
mitiglinide, repaglinide, and nateglinide; second generation
sulphonylureas such as glibenclamide, glipizide, gliclazide, and
glimiperide; glucagon-like peptide (GLP-1) analogues such as exenatide;
and other hypoglycaemics which are used as adjuncts to metformin therapy.
However, the use of a low dose antidiabetic agent in combination with a
biguanide poses a content uniformity challenge in the final dosage form.

[0013] U.S. Publication No. 2009/0221652 covers a combination of metformin
and meglitinide.

[0014] U.S. Pat. No. 6,677,358 relates to combinations of a long-acting
and a short-acting hypoglycemic agent. It covers a pharmaceutical
composition comprising repaglinide and metformin together with a suitable
carrier.

[0016] PCT Publication Nos. WO 2004/026241 and WO 99/47125, U.S.
Publication Nos. 2005/0249809 and 2004/0161462, and U.S. Pat. No.
6,099,862 disclose a metformin extended-release tablet coated with an
immediate-release coating containing an antihyperglycemic or a
hypoglycemic drug. The metformin cores are present as osmotic cores.

[0017] Although the prior art teaches pharmaceutical compositions that
contain both a biguanide and a low dose antidiabetic agent, there is a
need in the art to develop drug formulations in which biguanide is
present in an extended-release form and a low dose antidiabetic agent is
present in an immediate-release form that involves simple methods of
production and are cost effective. There is also a need for a solution to
the challenges of large-sized dosage forms and content uniformity issues
in the final dosage. The present invention teaches a pharmaceutical
composition comprising a biguanide and a low dose antidiabetic agent that
overcomes the problems in the prior art by eliminating content uniformity
issues in the dosage form, and reducing the size of the drug product for
increased patient compliance.

SUMMARY OF THE INVENTION

[0018] In one general aspect, the present invention provides for a
pharmaceutical composition that includes a biguanide in an
extended-release form and a low dose antidiabetic agent in an
immediate-release form.

[0019] In another general aspect, the present invention provides for a
pharmaceutical composition of a biguanide and a low dose antidiabetic
agent that includes:

[0020] (i) a biguanide core which includes a
therapeutically effective amount of biguanide or its pharmaceutically
effective salts and one or more pharmaceutically acceptable excipients;

[0021] (ii) optionally a seal coat;

[0022] (iii) an extended-release coat
which includes one or more rate-controlling materials wherein there is no
passageway in the coat;

[0023] (iv) optionally a second seal coat;

[0024]
(v) a low dose antidiabetic agent coat which includes a therapeutically
effective amount of a low dose antidiabetic agent or its pharmaceutically
effective salts and one or more pharmaceutically acceptable excipients;
and

[0025] (vi) optionally a film coat.

[0026] Embodiments of the composition may include one or more of the
following features. For example, the composition may be in the form of
tablets or capsules. The capsules may include one or more of aggregated
particles, pellets, mini tablets, tablets, beads, or granules.

[0027] In one embodiment, the biguanide may be layered onto a
pharmaceutically inert core or seed. The inert core or seed may be
hydrosoluble or hydroinsoluble.

[0028] The biguanide core of the present invention may include one or more
pharmaceutically acceptable excipients selected from one or more of
fillers, binders, disintegrants, anti adherents, lubricants, glidants,
osmogents, coloring agents, and flavoring agents.

[0029] The biguanide core may additionally contain one or more absorption
enhancers and/or one or more swellable polymers.

[0030] The seal coat may be applied over the biguanide core or over the
extended-release coat.

[0031] The rate-controlling materials used in the composition include
hydrophilic polymers, hydrophobic polymers, water-swellable polymers,
other hydrophobic materials, or mixtures thereof.

[0032] The biguanide used in the composition may include metformin,
phenformin, or buformin, and their pharmaceutically acceptable salts,
solvates, polymorphs, enantiomers, isomers, or mixtures thereof. For
example, the biguanide is metformin or its pharmaceutically acceptable
salts, solvates, polymorphs, enantiomers, isomers, or mixtures thereof.

[0033] The low dose antidiabetic agent used in the composition may include
DPP-IV inhibitors such as sitagliptin, linagliptin, vildagliptin,
saxagliptin, alogliptin, or dutogliptin; meglitinides such as
mitiglinide, repaglinide, or nateglinide; second generation
sulphonylureas such as glibenclamide, glipizide, gliclazide, or
glimiperide; glucagon-like peptide (GLP-1) analogues such as exenatide;
other hypoglycaemics which are used as an adjunct to metformin therapy;
or mixtures thereof. Particularly, the low dose antidiabetic agent is a
DPP-IV inhibitor or its pharmaceutically acceptable salts, solvates,
polymorphs, enantiomers, isomers, or mixtures thereof. More particularly,
the low dose antidiabetic agent is linagliptin.

[0034] The biguanide core may include a mixture of biguanide and a low
dose antidiabetic agent or the low dose antidiabetic agent coat may
include a mixture of a low dose antidiabetic agent and biguanide or both
the biguanide core and a low dose antidiabetic agent coat may include a
mixture of biguanide and a low dose antidiabetic agent.

[0035] The pharmaceutical composition of the present invention may further
include an additional antidiabetic agent.

[0036] In another aspect, the present invention relates to a
pharmaceutical composition of a biguanide and a low dose antidiabetic
agent that includes:

[0037] (i) a biguanide core which includes a
therapeutically effective amount of a biguanide or its pharmaceutically
effective salts and one or more pharmaceutically acceptable excipients;

[0038] (ii) optionally a seal coat;

[0039] (iii) an extended-release coat
which includes one or more rate-controlling materials wherein there is no
passageway in the coat;

[0040] (iv) optionally a second seal coat;

[0041]
(v) an immediate-release drug coat which includes a biguanide and a low
dose antidiabetic agent or its pharmaceutically effective salts and one
or more pharmaceutically acceptable excipients; and

[0042] (vi)
optionally a film coat.

[0043] In one embodiment, the ratio of biguanide in the core to that in
the coat ranges from about 99:1 to about 60:40.

[0044] In another general aspect, the present invention provides for a
process for preparing a pharmaceutical composition. The process includes
the steps of:

[0045] (i) preparing the cores which include a biguanide
or its pharmaceutically effective salts and one or more pharmaceutically
acceptable excipients;

[0046] (ii) optionally coating the cores with a
seal coat;

[0047] (iii) coating the biguanide cores of step (ii) with an
extended-release coating composition which includes one or more
rate-controlling materials;

[0048] (iv) coating the extended-release core
with an immediate-release coating composition which includes a low dose
antidiabetic agent or its pharmaceutically effective salts and one or
more pharmaceutically acceptable excipients; and

[0049] (v) optionally
providing a film coat.

[0050] In another general aspect, the present invention provides for a
method for treating diabetes by administering to a person in need thereof
a pharmaceutical composition of a biguanide and a low dose antidiabetic
agent. The composition includes:

[0051] (i) a biguanide core which
includes a therapeutically effective amount of biguanide or its
pharmaceutically effective salts and one or more pharmaceutically
acceptable excipients;

[0052] (ii) optionally a seal coat;

[0053] (iii)
an extended-release coat which includes one or more rate-controlling
materials wherein there is no passageway in the coat;

[0054] (iv) a low
dose antidiabetic agent coat which includes a therapeutically effective
amount of a low dose antidiabetic agent or its pharmaceutically effective
salts and one or more pharmaceutically acceptable excipients; and

[0055]
(v) optionally a film coat.

[0056] The details of one or more embodiments of the inventions are set
forth in the description below. Other features and objects of the
invention will be apparent from the description and examples.

DESCRIPTION OF THE INVENTION

[0057] The present invention provides for a pharmaceutical composition
that includes a biguanide in extended-release form and a low dose
antidiabetic agent in an immediate-release form.

[0058] The present invention also provides for a pharmaceutical
composition of a biguanide and a low dose antidiabetic agent that
includes:

[0059] (i) a biguanide core which includes a therapeutically
effective amount of biguanide or its pharmaceutically effective salts and
one or more pharmaceutically acceptable excipients;

[0060] (ii)
optionally a seal coat;

[0061] (iii) an extended-release coat which
includes one or more rate-controlling materials wherein there is no
passageway in the coat;

[0062] (iv) optionally a second seal coat;

[0063]
(v) a low dose antidiabetic agent coat which includes a therapeutically
effective amount of a low dose antidiabetic agent or its pharmaceutically
effective salts and one or more pharmaceutically acceptable excipients;
and

[0064] (vi) optionally a film coat.

[0065] The biguanide used in the composition may include metformin,
phenformin, or buformin and their pharmaceutically acceptable salts,
solvates, polymorphs, enantiomers, isomers, or mixtures thereof. For
example, the biguanide may be metformin or its pharmaceutically
acceptable salts, solvates, polymorphs, enantiomers, isomers, or mixtures
thereof. The amount of the biguanide in the present composition may range
from about 25 mg to about 2,000 mg.

[0066] The extended-release biguanide core may be present as aggregated
particles, pellets, mini tablets, tablets, beads, or granules.
Alternatively, the biguanide may be layered onto a pharmaceutically inert
core or seed. The inert core or seed may be hydrosoluble or
hydroinsoluble.

[0069] The biguanide core of the present invention includes one or more
pharmaceutically acceptable excipients. The pharmaceutically acceptable
excipients are known to those skilled in the art and may be selected from
one or more of fillers, diluents, binders, disintegrants, anti adherents,
lubricants, glidants, osmogents, coloring agents, and flavoring agents.

[0078] The biguanide core may additionally contain one or more swellable
polymers. The term "swellable polymer" refers to polymers that gel,
swell, or expand in the presence of water or biological fluids. The
swellable polymers include high molecular weight hydroxpropyl
methylcellulose, high molecular weight polyethylene oxides (such as
POLYOX® WSR-301, WSR-303 or WSR Coagulant), hydroxypropylcellulose,
hydroxyethylcellulose, sodium carboxymethylcellulose, xanthan gum,
polyvinyl acetate, or mixtures thereof.

[0079] The biguanide core may be prepared by any pharmaceutically
acceptable technique that achieves uniform blending, e.g., dry blending,
dry granulation, wet granulation, compaction, or fluidized bed
granulation. For example, the core formulation of the present invention
is fabricated by compression into tablets.

[0080] Examples of solvents used for preparing the biguanide core include
methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water,
or mixtures thereof. Preferably, purified water is used as the solvent.

[0081] The biguanide core is coated with an extended-release coating
composition with percentage weight gain of about 1% to about 40% w/w.

[0082] The rate-controlling materials used in the extended-release coat
composition are selected from one or more of hydrophilic polymers,
hydrophobic polymers, water swellable polymers, other hydrophobic
materials, or mixtures thereof. The rate-controlling material may be
present in a concentration from about 1% to about 30% w/w of the total
composition.

[0083] The extended-release coat is permeable to the passage of water,
biological fluids, and active ingredient in the core. Further, the
extended-release coat does not contain any passageway.

[0086] Examples of water-swellable polymers include polyethylene oxide
having a molecular weight of from 100,000 to 8,000,000; poly(hydroxy
alkyl methacrylate) having a molecular weight of from 30,000 to
5,000,000; poly(vinyl) alcohol having a low acetal residue, which is
cross-linked with glyoxal, formaldehyde, or glutaraldehyde and having a
degree of polymerization of from 200 to 30,000; a mixture of methyl
cellulose, cross-linked agar, and carboxymethyl cellulose; a water
insoluble, water-swellable copolymer produced by forming a dispersion of
a finely divided copolymer of maleic anhydride with styrene, ethylene,
propylene, butylene, or isobutylene cross-linked with from 0.001 to 0.5
moles of saturated cross-linking agent per mole of maleic anhydride in
the copolymer; Carbopol® carbomer which is an acidic carboxy polymer
having a molecular weight of from 450,000 to 4,000,000; Cyanamer®
polyacrylamides; cross-linked water-swellable indene-maleic anhydride
polymers; polyacrylic acid having a molecular weight of from 80,000 to
200,000; starch graft copolymers; acrylate polymer polysaccharides
composed of condensed glucose units such as diester cross-linked
polyglucan and the like; Amberlite® ion exchange resins;
Explotab® sodium starch glycolate; Ac-Di-Sol® croscarmellose
sodium; and combinations thereof.

[0090] The coating compositions may be coated on the biguanide core by
conventional methods such as drug layering, dry compression, deposition,
and printing.

[0091] The coating composition may be applied as a solution or dispersion
of rate-controlling materials. Examples of solvents used for preparing a
solution or dispersion of rate-controlling materials include methylene
chloride, isopropyl alcohol, acetone, methanol, ethanol, water, or
mixtures thereof.

[0092] A seal coating composition may be coated over the biguanide core or
over the extended-release coat. The polymers used to provide seal coating
may include one or more hydrophilic polymers. Examples of hydrophilic
polymers include hydroxypropylcellulose, hydroxypropylisopropylcellulose,
methoxypropyl cellulose, hydroxypropylmethylcellulose,
hydroxypropylpentylcellulose, hydroxypropylhexylcellulose, or mixtures
thereof. The seal coating may optionally be opacified.

[0093] The extended-release biguanide core is coated with an
immediate-release drug layer. The immediate-release drug layer comprises
a therapeutically effective amount of a low dose antidiabetic agent and
optionally a biguanide.

[0094] The low dose antidiabetic agents used in the composition include,
but are not limited to, thiazolidinediones such as troglitazone,
rosiglitazone, or pioglitazone; dipeptidyl peptidase-IV (DPP-IV)
inhibitors such as sitagliptin, linagliptin, vildagliptin, saxagliptin,
alogliptin, or dutogliptin; meglitinides such as mitiglinide,
repaglinide, or nateglinide; second generation sulphonylureas such as
glibenclamide, glipizide, gliclazide, or glimepiride glucagon-like
peptide (GLP-1) analogues such as exenatide; and other hypoglycaemics
which are used as an adjunct to metformin therapy. The amount of the low
dose antidiabetic agent used in the present composition may range from
about 1 mg to about 200 mg.

[0095] Further, a portion of biguanide may also be present in the
immediate-release drug layer along with the low dose antidiabetic agent.
The addition of a portion of biguanide in the coat results in reduction
of core size and overall dosage form size, resulting in improved patient
compliance.

[0096] The present invention also encompasses a composition comprising an
extended-release biguanide layer and an immediate-release drug layer
comprising a biguanide and a low dose antidiabetic agent. The biguanide
used in the core and the coat may be similar or different. The ratio of
biguanide in the core to that in the coat ranges from about 99:1 to about
60:40.

[0097] The term "about", as used herein, when used along with the values
assigned to certain measurements and parameters means a variation of up
to 10% from such values, or in the case of a range of values, means up to
a 10% variation from both the lower and upper limits of such ranges.

[0098] The low dose antidiabetic agent coat includes a therapeutically
effective amount of a low dose antidiabetic agent or its pharmaceutically
effective salts, optionally a biguanide, and one or more pharmaceutically
acceptable excipients known to those skilled in the art, which may be
selected from one or more of wicking agents, wetting agents,
plasticizers, opacifiers and colorants.

[0100] Examples of wetting agents include hydrophilic surfactants,
hydrophobic surfactants, or mixtures thereof. The hydrophilic surfactants
may be selected from one or more of non-ionic surfactants, ionic
surfactants, or mixtures thereof.

[0107] The immediate-release drug layer may further include one or more
film-forming polymers. The film-forming polymers may be hydrophilic
polymers.

[0108] The low dose antidiabetic agent coating composition may be applied
as a solution or dispersion over the extended-release coat. Examples of
solvents used for preparing a solution or dispersion of a low dose
antidiabetic agent include methylene chloride, isopropyl alcohol,
acetone, methanol, ethanol, water, or mixtures thereof.

[0109] The pharmaceutical composition may optionally be coated with one or
more layers of a film coat comprising film forming agents and/or
pharmaceutically acceptable excipients.

[0111] The film forming agents may be applied as a solution or dispersion
of coating ingredients. Examples of solvents used for preparing a
solution or dispersion of the coating ingredients include methylene
chloride, isopropyl alcohol, acetone, methanol, ethanol, water, or
mixtures thereof.

[0112] The various coats of the composition may be coated using a
conventional coating pan, a spray coater, a rotating perforated pan, an
automated system such as a centrifugal fluidizing (CF) granulator, a
fluidized bed process, or any other suitable automated coating equipment.

[0113] The various compositions described above are used for treating
diabetes.

[0114] The present invention is illustrated below by reference to the
following examples. However, one skilled in the art will appreciate that
the specific methods and results discussed are merely illustrative of the
invention, and not to be construed as limiting the invention.

[0117] 1. Metformin hydrochloride and microcrystalline cellulose were
mixed uniformly and granulated with a polyvinylpyrrolidone solution in
water. 2. The granules were dried in the fluidized bed dryer and the
dried granules were mixed with hydrophobic colloidal silicon dioxide and
magnesium stearate. 3. The blend of step 2 was compressed into core
tablets.

ER Coating:

[0118] 4. Ethyl cellulose, hydroxypropyl methylcellulose, and talc were
dispersed in an isopropyl alcohol:water mixture. 5. The tablets of step 3
were coated with the dispersion of step 4.

Active Coat:

[0119] 6. The isopropyl alcohol:water mixture was taken in a container and
hydroxypropyl methylcellulose E-5 was added to it, followed by
Polysorbate-80 and pioglitazone hydrochloride. 7. The ER coated tablets
were coated with the dispersion of step 6 in a pan coater.

[0123] 1. Metformin hydrochloride, sodium carboxymethyl cellulose,
microcrystalline cellulose and hydroxypropyl methylcellulose were mixed
uniformly and granulated with hydroxypropyl methylcellulose E-5. 2. The
granules were dried in a fluidized bed dryer and lubricated with
magnesium stearate and silicon dioxide. 3. The blend of step 2 was
compressed into core tablets.

ER Coating:

[0124] 4. Ethyl Cellulose, hydroxypropyl methylcellulose and talc were
dispersed in an isopropyl alcohol:water mixture. 5. The tablets of step 3
were coated with the dispersion of step 4.

Pioglitazone Coating:

[0125] 6. The isopropyl alcohol:water mixture was taken in a container and
hydroxypropyl methylcellulose was added to it followed by polysorbate-80
and pioglitazone hydrochloride. 7. The ER coated tablets were coated with
the dispersion of step 6 in a pan coater.

[0129] 1. Metformin hydrochloride, sodium lauryl sulphate, and sodium
chloride were mixed uniformly and granulated with polyvinylpyrrolidone in
a rapid mixer granulator. 2. The granules were dried in a fluidized bed
dryer and lubricated with magnesium stearate. 3. The blend of step 2 was
compressed into core tablets.

ER Coating:

[0130] 4. Ethyl Cellulose, hydroxypropyl methylcellulose, diethyl
phthalate, and talc were dispersed in an isopropyl alcohol:water mixture.
5. The tablets of step 3 were coated with the dispersion of step 4.

Pioglitazone Layer:

[0131] 6. Pioglitazone hydrochloride, hydroxypropyl methylcellulose,
polysorbate 80, and talc were dispersed in an isopropyl alcohol:water
mixture. 7. The ER coated tablets were coated with the dispersion of step
6.

[0134] 1. Metformin hydrochloride, microcrystalline cellulose, and sodium
lauryl sulphate were mixed uniformly and granulated with a
polyvinylpyrrolidone solution in isopropyl alcohol. 2. The granules were
dried in a fluidized bed dryer and lubricated with magnesium stearate. 3.
The blend of step 2 was compressed into core tablets.

ER Coating:

[0135] 4. Cellulose acetate was dissolved in acetone followed by addition
of triacetin, polyethylene glycol, water, and hydroxypropyl
methylcellulose under stirring. 5. The tablets of step 3 were coated with
the dispersion of step 4.

Pioglitazone Layer:

[0136] 6. Hydroxypropyl methylcellulose and sodium lauryl sulphate were
dissolved in water followed by the addition of isopropyl alcohol. 7.
Pioglitazone hydrochloride was dispersed into the solution of step 6. 8.
The ER coated tablets were coated with the dispersion of step 7.

[0139] 1. Metformin hydrochloride, microcrystalline cellulose, and sodium
lauryl sulphate were mixed uniformly and granulated with a
polyvinylpyrrolidone solution in isopropyl alcohol. 2. The granules were
dried in a fluidized bed dryer and lubricated with magnesium stearate. 3.
The blend of step 2 was compressed into core tablets.

Seal Coating:

[0140] 4. Hydroxypropyl methylcellulose was dissolved in isopropyl
alcohol. 5. The tablets of step 3 were coated with the dispersion of step
4.

ER Coating:

[0141] 6. Cellulose acetate was dissolved in acetone followed by the
addition of triacetin, polyethylene glycol, water, and hydroxypropyl
methylcellulose under stirring. 7. The seal coated tablets of step 5 were
coated with the dispersion of step 6.

Pioglitazone Layer:

[0142] 8. Lactose, hydroxypropyl cellulose, and sodium lauryl sulphate
were dissolved in water/non-aqueous solvent. 9. Pioglitazone
hydrochloride was dispersed into the solution of step 8. 10. The ER
coated tablets were coated with the dispersion of step 9.

[0145] 1. Metformin hydrochloride, microcrystalline cellulose, and sodium
lauryl sulphate were mixed uniformly and granulated with a
polyvinylpyrrolidone solution in isopropyl alcohol. 2. The granules were
dried in a fluidized bed dryer and lubricated with magnesium stearate. 3.
The blend of step 2 was compressed into core tablets.

Seal Coating:

[0146] 4. Hydroxypropyl methylcellulose was dissolved in isopropyl
alcohol. 5. The tablets of step 3 were coated with the s dispersion of
step 4.

ER Coating:

[0147] 6. Cellulose acetate was dissolved in acetone followed by the
addition of triacetin and polyethylene glycol under stirring. 7. The seal
coated tablets of step 5 were coated with the dispersion of step 6.

Pioglitazone Layer:

[0148] 8. Lactose and hydroxypropylcellulose were dissolved in water. 9.
Pioglitazone hydrochloride was dispersed into the solution of step 8. 10.
The ER coated tablets were coated with the dispersion of step 9.

[0151] 1. Metformin hydrochloride, microcrystalline cellulose, and sodium
lauryl sulphate were mixed uniformly and granulated with a
polyvinylpyrrolidone solution in isopropyl alcohol. 2. The granules were
dried in a fluidized bed dryer and lubricated with magnesium stearate. 3.
The blend of step 2 was compressed into core tablets.

Seal Coating:

[0152] 4. Hydroxypropyl methylcellulose was dissolved in isopropyl
alcohol. 5. The tablets of step 3 were coated with the dispersion of step
4.

ER Coating:

[0153] 6. Cellulose acetate was dissolved in acetone followed by the
addition of triacetin and polyethylene glycol under stirring. 7. The seal
coated tablets of step 5 were coated with the dispersion of step 6.

Pioglitazone Layer:

[0154] 8. Lactose, hydroxypropylcellulose, and silicon dioxide were
dissolved in water. 9. Pioglitazone hydrochloride was dispersed into the
solution of step 8. 10. The ER coated tablets were coated with the
dispersion of step 9.

[0157] 1. Metformin hydrochloride and sodium lauryl sulphate were mixed
uniformly and granulated with a polyvinylpyrrolidone solution in purified
water. 2. The granules were dried in a fluidized bed dryer and lubricated
with magnesium stearate. 3. The blend of step 2 was compressed into core
tablets.

Seal Coating:

[0158] 4. Hydroxypropyl methylcellulose was dispersed in isopropyl alcohol
followed by the addition of purified water. 5. The tablets of step 3 were
coated with the dispersion of step 4.

ER Coating:

[0159] 6. Cellulose acetate was dissolved in acetone followed by the
addition of triacetin and polyethylene glycol under stirring. 7, Purified
water was added slowly under stirring to the dispersion of step 6. 8. The
seal coated tablets of step 5 were coated with the dispersion of step 7.

Pioglitazone Layer:

[0160] 9. Lactose and hydroxypropyl cellulose were dissolved in purified
water. 10. Pioglitazone hydrochloride was dispersed into the solution of
step 9. 11. The ER coated tablets were coated with the dispersion of step
10.

Film Coating:

[0161] 12. A film coating solution was prepared by dispersing Opadry®
white in purified water. 13. The pioglitazone coated tablets were coated
with the solution of step 12.

[0164] 1. Metformin hydrochloride, hydroxypropyl methylcellulose, and
polyvinylpyrrolidone were mixed uniformly and granulated with purified
water. 2. The granules were dried in a fluidized bed dryer and were mixed
with hydroxypropyl methylcellulose and sodium lauryl sulphate followed by
lubrication with magnesium stearate. 3. The blend of step 2 was
compressed into core tablets.

Seal Coating:

[0165] 4. The tablets of step 3 were coated with a hydro-alcoholic
solution of hydroxypropyl methylcellulose.

ER Coating:

[0166] 5. Ethyl cellulose, hydroxypropyl methylcellulose, and tri-ethyl
citrate were dispersed in isopropyl alcohol:water. 6. The seal coated
tablets of step 4 were coated with the dispersion of step 5.

Twin Drug Layering:

[0167] 7. Metformin hydrochloride and hydroxypropylcellulose were
dissolved in purified water followed by the addition of Tween-80. 8.
Linagliptin was dissolved in ethanol followed by the addition of the
resulting solution to the solution of step 7. 9. The ER coated tablets
were coated with the dispersion of step 8.

[0168] While several particular forms of the invention have been
illustrated and described, it will be apparent that various modifications
and combinations of the invention detailed in the text can be made
without departing from the spirit and scope of the invention.